title: Thyroid hormone signalling is altered in response to physical training in patients with end-stage heart failure and mechanical assist devices: potential physiological consequences?
abstract: OBJECTIVE
  The present study investigated the potential of the failing myocardium of patients with ventricular assist devices (VAD) to respond to physiological growth stimuli, such as exercise, by activating growth signalling pathways. This may be of therapeutic relevance in identifying novel pharmacological targets for therapies that could facilitate recovery after VAD implantation.
  
  
  METHODS
  Twenty-two patients bridged to heart transplantation (HTx) with VAD were included in the study. A group of patients underwent moderate intensity aerobic exercise (GT), while another group of patients did not receive exercise training (CG). Thyroid hormone receptor alpha1 (TRα1) protein and total (t) and phosphorylated (p) protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) kinase signalling were measured in myocardial tissue by western blotting at pre-VAD and pre-HTx period. In addition, Thyroid hormone (TH) levels were measured in plasma.
  
  
  RESULTS
  Peak oxygen consumption (VO2) at pre-HTx period was higher in patients subjected to training protocol [18.0 (0.8) for GT when compared with 13.7 (0.7) for CG group, P = 0.002]. N-terminal-prohormone of brain natriuretic peptide (NT-proBNP) levels were 1068 (148) for CG vs 626 (115) for GT group, P = 0.035. A switch towards up-regulation of physiological growth signalling was observed: the ratio of p-Akt/t-Akt was 2-fold higher in GT vs CG, P < 0.05 while p-JNK/t-JNK was 2.5-fold lower (P < 0.05) in GT vs CG, in pre-HTx samples. This response was accompanied by a 2.0-fold increase in TRα1 expression in pre-HTx samples with concomitant increase in circulating T3 in GT vs CG, P < 0.05. No differences in peak VO2, NT-proBNP, T3, TRα1, p/t-AKT and p/t-JNK were found between groups in the pre-VAD period.
  
  
  CONCLUSIONS
  The unloaded failing myocardium responded to physical training by enhancing thyroid hormone signalling. This response was associated with an up-regulation of Akt and suppression of JNK activation.
authors.affiliation: Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece.
authors.forename: Stamatios
authors.initials: S
authors.lastname: Adamopoulos
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Gouziouta
authors.forename: Polixeni
authors.initials: P
authors.lastname: Mantzouratou
authors.forename: Ioannis D
authors.initials: ID
authors.lastname: Laoutaris
authors.forename: Athanasios
authors.initials: A
authors.lastname: Dritsas
authors.forename: Dennis V
authors.initials: DV
authors.lastname: Cokkinos
authors.forename: Iordanis
authors.initials: I
authors.lastname: Mourouzis
authors.forename: Petros
authors.initials: P
authors.lastname: Sfyrakis
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iervasi
authors.forename: Constantinos
authors.initials: C
authors.lastname: Pantos
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D005081:Exercise Therapy; D005260:Female; D006115:Greece; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000097:blood; D010766:Phosphorylation; D011446:Prospective Studies; D011474:Prosthesis Design; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood*; D016896:Treatment Outcome; D016276:Ventricular Function
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Exercise training; Heart failure; Kinase signalling; Thyroid hormone; Thyroid hormone receptor alpha1